title: Replication-associated mutational asymmetry in the human genome.
abstract: During evolution, mutations occur at rates that can differ between the two DNA strands. In the human genome, nucleotide substitutions occur at different rates on the transcribed and non-transcribed strands that may result from transcription-coupled repair. These mutational asymmetries generate transcription-associated compositional skews. To date, the existence of such asymmetries associated with replication has not yet been established. Here, we compute the nucleotide substitution matrices around replication initiation zones identified as sharp peaks in replication timing profiles and associated with abrupt jumps in the compositional skew profile. We show that the substitution matrices computed in these regions fully explain the jumps in the compositional skew profile when crossing initiation zones. In intergenic regions, we observe mutational asymmetries measured as differences between complementary substitution rates; their sign changes when crossing initiation zones. These mutational asymmetries are unlikely to result from cryptic transcription but can be explained by a model based on replication errors and strand-biased repair. In transcribed regions, mutational asymmetries associated with replication superimpose on the previously described mutational asymmetries associated with transcription. We separate the substitution asymmetries associated with both mechanisms, which allows us to determine for the first time in eukaryotes, the mutational asymmetries associated with replication and to reevaluate those associated with transcription. Replication-associated mutational asymmetry may result from unequal rates of complementary base misincorporation by the DNA polymerases coupled with DNA mismatch repair (MMR) acting with different efficiencies on the leading and lagging strands. Replication, acting in germ line cells during long evolutionary times, contributed equally with transcription to produce the present abrupt jumps in the compositional skew. These results demonstrate that DNA replication is one of the major processes that shape human genome composition.
authors.affiliation: Centre de Génétique Moléculaire, Centre National de la Recherche Scientifique (CNRS), Gif-sur-Yvette, France.
authors.forename: Chun-Long
authors.initials: CL
authors.lastname: Chen
authors.forename: Lauranne
authors.initials: L
authors.lastname: Duquenne
authors.forename: Benjamin
authors.initials: B
authors.lastname: Audit
authors.forename: Guillaume
authors.initials: G
authors.lastname: Guilbaud
authors.forename: Aurélien
authors.initials: A
authors.lastname: Rappailles
authors.forename: Antoine
authors.initials: A
authors.lastname: Baker
authors.forename: Maxime
authors.initials: M
authors.lastname: Huvet
authors.forename: Yves
authors.initials: Y
authors.lastname: d'Aubenton-Carafa
authors.forename: Olivier
authors.initials: O
authors.lastname: Hyrien
authors.forename: Alain
authors.initials: A
authors.lastname: Arneodo
authors.forename: Claude
authors.initials: C
authors.lastname: Thermes
mesh_terms: D001482:Base Composition; D002460:Cell Line; D004261:DNA Replication / Q000235:genetics*; D019143:Evolution, Molecular; D015894:Genome, Human / Q000235:genetics*; D005854:Germ Cells / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D020014:K562 Cells; D008957:Models, Genetic; D009154:Mutation / Q000235:genetics*; D009928:Organ Specificity / Q000235:genetics